Glial Cells and Polyamine Signaling in the Central Nervous System

项目摘要/摘要（来自父母补助金）： 最近出现的出版物表明，多胺（PA）是非常常见的 衰老障碍和HIV相关的神经认知障碍（HAND）、阿尔茨海默病、亨廷顿病和 帕金森病以及Snyder-Robinson综合征和SEEAST/EAST综合征。保护区整体放行 在神经元活动和创伤过程中从未知来源的大脑中。PA表现出神经保护作用， 神经毒性、局部缺血、脑损伤，并且还延长寿命。由于PA含量随着老化或老化过程而下降， 在病理学上，PA提供的神经保护也会下降。这大大增加了以下风险： 发病率和死亡率。尽管PA在公共卫生中具有重要意义，但对大脑中PA通量的了解相对较少 而对CNS中的神经胶质细胞关注不够。 有趣的是，我们发现在健康的成年人大脑和视网膜中，神经胶质细胞而不是神经元积累 优选PA如亚精胺（SD）和精胺（SP）。我们最近进一步发现，PA是 星形胶质细胞连接蛋白-43（Cx43）间隙连接（GJ）的主要开放因子。因此，由于Cx43 GJ是主要的 作为星形胶质细胞之间的沟通渠道，PA保持胶质细胞合胞体的完整性，可能有助于保持健康 大脑状态，然而在许多（病理）生理条件下，情况没有得到很好的研究。 内部PA的储存及其受胶质细胞调节对脑功能的影响是研究的一部分。 剩余的谜团和我们的发现提出了关键问题：（i）这种现象背后的机制是什么？ PA在星形胶质细胞和神经元之间的不均匀分布和积聚？(ii)有哪些机制 中枢神经系统中神经胶质细胞释放PA的能力？(iii)脑内PA通量对神经元的影响是什么？ 功能？以及（iv）最终，PA在大脑紊乱和疾病中的作用是什么？ 神经胶质PA通路迄今一直被忽视，虽然很明显，这些分子是关键， 元素正常的大脑状态和他们的代谢紊乱，显然，导致许多发展 病理综合征和疾病。我们已经开发出测量脑切片中PA通量的技术 和视网膜，并将使用转基因动物模型的手（和在未来的其他疾病），以研究 PA易位的病理生理学。在这个项目中，我们将测试原来的假设，即PA是新颖的 “胶质递质”，其（i）被转运到胶质细胞中，（ii）开放的星形胶质细胞间缝隙连接，（iii） 在星形胶质细胞-星形胶质细胞合胞体（AIM-1）中传播和（iv）在局部刺激后从胶质细胞释放 (v)调节神经胶质网络（AIM-2）。 我们将解决这两个目标，以确定PA摄取/积累/释放/信号转导的机制， CNS。这些研究将为研究生带来新的科学知识和研究机会， 进一步了解神经退行性过程，帮助推进诊断，治疗和预防。

Project Summary/Abstract (from Parent grant): Emerging recent publications show that polyamines (PAs) are key players in the exceedingly common disorders of aging and HIV associated neurocognitive disorders (HAND), Alzheimer's, Huntington's and Parkinson diseases as well as in Snyder-Robinson and SeSAME/EAST syndromes. PAs are released in whole brain from unknown sources during neuronal activity and trauma. PAs demonstrate neuroprotection against neurotoxicity, ischemia, brain injury and also increase longevity. Since PA content declines with aging or during pathology, the neuroprotection afforded by PAs can decline as well. This substantially increases the risk of morbidity and mortality. Despite its public health importance, relatively little is known about PA fluxes in brain and insufficient attention is paid to glial cells in CNS. Intriguingly, we found that in healthy adult brain and retina, glial cells but not neurons accumulate preferentially PAs such as spermidine (SD) and spermine (SP). We further recently found that PAs are the major openers of astrocytic connexin-43 (Cx43) gap junctions (GJs). Therefore, since Cx43 GJs are the major communicating channels between astrocytes, PAs keep glial syncytium integrity that may help to hold healthy brain status, however in many (patho)physiological conditions the situations are not well studied. The storage of internal PAs and their effects regulated by glia on brain function are some of the remaining mysteries and our findings raise key questions: (i) What are the mechanisms that underlie such uneven distribution and accumulation of PAs between astrocytes and neurons? (ii) What are the mechanisms of PA release in CNS from glia? (iii) What are the consequences of PA fluxes within the brain on neuronal function? and (iv) Ultimately, what are the roles of PAs in brain disorders and diseases? The glial PA pathways hitherto have been neglected, although it is evident that these molecules are key elements for normal brain status and their metabolic disorders, apparently, cause the development of many pathological syndromes and diseases. We have developed techniques for measuring PA fluxes in brain slices and retina and will use transgenic animal models of HAND (and in the future of other diseases) to study (patho)physiology of PA translocation. In this project, we will test the original hypothesis that PAs are novel “gliotransmitters” that (i) are transported into glia, (ii) open astrocytic intercellular gap junctions, (iii) propagate in the astrocyte-to-astrocyte syncytium (AIM-1) and (iv) are released from glia upon local stimulation (v) to regulate the neuronal-glial network (AIM-2). We will address these two aims to determine mechanisms of PA uptake/accumulation/release/signaling in CNS. The studies will lead to new scientific knowledge and research opportunities for graduate students to further understand neurodegenerative processes, helping advance diagnosis, treatment and prevention.